crossing96/oncoscreening huggingface dataset:
Melatonin inhibits bladder tumorigenesis by suppressing PPARγ/ENO1-mediated glycolysis.	Melatonin is a well-known natural hormone, which shows a potential anticancer effect in many human cancers. Bladder cancer (BLCA) is one of the most malignant human cancers in the world. Chemoresistance is an increasingly prominent phenomenon that presents an obstacle to the clinical treatment of BLCA. There is an urgent need to investigate novel drugs to improve the current clinical status. In our study, we comprehensively explored the inhibitory effect of melatonin on BLCA and found that it could suppress glycolysis process. Moreover, we discovered that ENO1, a glycolytic enzyme involved in the ninth step of glycolysis, was the downstream effector of melatonin and could be a predictive biomarker of BLCA. We also proved that enhanced glycolysis simulated by adding exogenous pyruvate could induce gemcitabine resistance, and melatonin treatment or silencing of ENO1 could intensify the cytotoxic effect of gemcitabine on BLCA cells. Excessive accumulation of reactive oxygen species (ROS) mediated the inhibitory effect of melatonin on BLCA cells. Additionally, we uncovered that PPARγ was a novel upstream regulator of ENO1, which mediated the downregulation of ENO1 caused by melatonin. Our study offers a fresh perspective on the anticancer effect of melatonin and encourages further studies on clinical chemoresistance.	bladder
PLCε promotes the Warburg effect and tumorigenesis through AKT/GSK3β/Cdc25a in bladder cancer.	Phospholipase C epsilon (PLCε) is a oncogene in various malignancies and regulates diverse cellular functions. But understanding of the relation between PLCε and glycolytic pathways has not been clearly identified. In the present study, we explored the effect of PLCε on the Warburg effect and tumorigenesis in bladder cancer (BCa). In our study, we showed that PLCε expression was elevated in BCa samples compared with matched adjacent nonmalignant bladder tissues. PLCε depletion using Lentivirus-shPLCε (LV-shPLCε) dramatically decreased cell growth, glucose consumption and lactate production, arresting T24 and BIU cells in the S phase of the cell cycle. We also observed that PLCε was correlated with the activation of protein kinase B (AKT) and cell division cycle 25 homolog A (Cdc25a) overexpression. In addition, we demonstrated that AKT/glycogen synthase kinase 3 beta (GSK3β)/Cdc25a signaling pathways are involved in the PLCε-mediated Warburg effect in BCa. Moreover, we showed that PLCε had an effect on tumorigenesis in in vivo experiments. In summary, our findings demonstrate that AKT/GSK3β/Cdc25a is critical for the effect PLCε on Warburg effect and tumorigenesis.	bladder
Immune Co-inhibitory Receptors CTLA-4, PD-1, TIGIT, LAG-3, and TIM-3 in Upper Tract Urothelial Carcinomas: A Large Cohort Study.	Programmed cell death 1 ligand 1), programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3, lymphocyte activation gene-3, and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in upper tract urothelial carcinoma (UTUC). The aim of this Cohort Study was to provide evidence concerning expression profiles and the clinical significance of CIRs among Chinese UTUC patients. A total of 175 UTUC patients who received radical surgery in our center were included. We used immunohistochemistry to evaluate CIR expressions in tissue microarrays (TMAs). Clinicopathological characteristics and prognostic correlations of CIR proteins were retrospectively analyzed. TIGIT, T-cell immunoglobulin and mucin-domain containing-3, PD-1, CTLA-4, Programmed cell death 1 ligand 1, and lymphocyte activation gene-3 high expression was examined in 136(77.7%), 86(49.1%), 57(32.6%), 18(10.3%), 28(16.0%), and 18(10.3%) patients, respectively. Log-rank tests and Multivariate Cox analysis both implied CTLA-4 and TIGIT expression was associated with worse relapse-free survival. In conclusion, this is the largest Chinese UTUC cohort study, and we analyzed the Co-inhibitory receptor expression profiles in UTUC. We identified CTLA-4 and TIGIT expression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced UTUCs are probably immunogenic, for which single or combined immunotherapy may be potential therapeutic approaches in the future.	bladder
Blood-based liquid biopsy: insights into early detection, prediction, and treatment monitoring of bladder cancer.	Bladder cancer (BC) is a clinical challenge worldwide with late clinical presentation, poor prognosis, and low survival rates. Traditional cystoscopy and tissue biopsy are routine methods for the diagnosis, prognosis, and monitoring of BC. However, due to the heterogeneity and limitations of tumors, such as aggressiveness, high cost, and limited applicability of longitudinal surveillance, the identification of tumor markers has attracted significant attention in BC. Over the past decade, liquid biopsies (e.g., blood) have proven to be highly efficient methods for the discovery of BC biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into the peripheral circulation and allows serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers are being extensively studied and have shown promising results in clinical applications of BC, including early detection, detection of microscopic residual disease, prediction of recurrence, and response to therapy. Therefore, in this review, we aim to provide an update on various novel blood-based liquid biopsy markers and review the advantages and current limitations of liquid biopsy in BC therapy. The role of blood-based circulating tumor cells, circulating tumor DNA, cell-free RNA, exosomes, metabolomics, and proteomics in diagnosis, prognosis, and treatment monitoring, and their applicability to the personalized management of BC, are highlighted.	bladder
Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers.	BACKGROUND: Radiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To analyze predictors of complete response (CR) and survival after RT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3-4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29-0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034-0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46-2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25-3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79-3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46-0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51-0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01-1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34-2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17-1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49-0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51-0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12-1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. CONCLUSIONS: RT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. PATIENT SUMMARY: We investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.	bladder
A comprehensive analysis of immunogenic cell death and its key gene HSP90AA1 in bladder cancer.	BACKGROUND: Bladder cancer (BLCA) is defined as a type of urinary cancer with high incidence and lack of specific biomarkers and drug targets. Immunogenic cell death (ICD) has been classified as a regulated type of cell death. Growing evidence suggested that ICD can reshape the tumor immune microenvironment, which may contribute to the development of immunotherapy strategies. The aim of this study was to reveal the specific mechanism of ICD in bladder cancer and to further predict the prognostic immunotherapy outcomes. METHODS: By consensus clustering analysis, bladder cancer patients in TCGA database were divided into different ICD subtypes. Additionally, we developed an ICD-scoring system and constructed the ICD score-based risk signature and nomogram to better characterize patients. Furthermore, we carried out a series of experiments to verify the relevant findings. RESULTS: Based on the transcriptome expression levels of ICD-related genes, a total of 403 BLCA patients in the TCGA database were divided into two subgroups with different ICD molecular patterns by consensus cluster analysis. These subgroups showed different clinicopathological features, survival outcomes, tumor microenvironment (TME) characteristics, immune-related scores, and treatment response. Moreover, the established prediction model and ICD score can effectively distinguish high risk/score patients from low risk/score patients, which has excellent predictive value. Finally, we found that the key gene HSP90AA1 was highly expressed in the high-ICD score group and in bladder cancer tissues, and was confirmed to be associated with the proliferation of bladder cancer cells. CONCLUSION: To sum up, we established a new classification system for BLCA based on ICD-related genes. This stratification has significant predictive power for clinical outcomes and can effectively evaluate the prognosis and immunotherapy of BLCA patients. Finally, it was proved that HSP90AA1 was highly expressed in BLCA and would be a promising therapeutic target for BLCA.	bladder
CircRPPH1 accelerates the proliferation and migration of bladder cancer via enhancing the STAT3 signaling pathway.	Bladder cancer (BCa) is a common malignant disease with high recurrence and variable prognosis. Circular RNAs (circRNAs) are implicated in the development of multiple diseases. However, the biological activities of circRNAs in BCa remain largely elusive. In the present study, it was found that circRPPH1 was upregulated in BCa cell lines compared with normal urothelial cells. CircRPPH1 downregulation could inhibit the proliferation, migration and invasion of BCa cells in vitro and in vivo. Mechanistically, it was demonstrated that circRPPH1 can act as a sponge of miR‑296‑5P to upregulate STAT3, and interact with FUS to promote phosphorylated (p)‑STAT3 nuclear transport. Overall, circRPPH1 could promote BCa progression through sponging miR‑296‑5p to upregulate the expression of STAT3 and interacting with FUS to promote p‑STAT3 nuclear transport. CircRPPH1 was first identified to play a tumorigenic role in BCa, which could be an underlying therapeutic target.	bladder
Bioengineered bacterial outer membrane vesicles encapsulated Polybia-mastoparan I fusion peptide as a promising nanoplatform for bladder cancer immune-modulatory chemotherapy.	BACKGROUND: Nanosized bacterial outer membrane vesicles (OMVs) secreted by Gram-negative bacteria have emerged as a novel antitumor nanomedicine reagent due to their immunostimulatory properties. The encapsulated bacterial composition in OMVs can be edited via manipulating bioengineering technology on paternal bacteria, allowing us to design an ingenious antitumor platform by loading the Polybia-mastoparan I (MPI) fusion peptide into OMVs. METHODS: OMVs containing the MPI fusion peptide were obtained from bioengineered Escherichia coli transformed with recombinant plasmid. The antitumor efficacy of bioengineered OMVs in vitro was verified by performing cell viability and wound-healing and apoptosis assays using MB49 and UMUC3 cells, respectively. Subcutaneous MB49 tumor-bearing mice were involved to investigate the tumor inhibition ability of bioengineered OMVs. Moreover, the activated immune response in tumor and the biosafety were also evaluated in detail. RESULTS: The resulting OMVs had the successful encapsulation of MPI fusion peptides and were subjected to physical characterization for morphology, size, and zeta potential. Cell viabilities of bladder cancer cells including MB49 and UMUC3 rather than a non-carcinomatous cell line (bEnd.3) were decreased when incubated with bioengineered OMVs. In addition, bioengineered OMVs restrained migration and induced apoptosis of bladder cancer cells. With intratumor injection of bioengineered OMVs, growths of subcutaneous MB49 tumors were significantly restricted. The inherent immunostimulation of OMVs was demonstrated to trigger maturation of dendritic cells (DCs), recruitment of macrophages, and infiltration of cytotoxic T lymphocytes (CTLs), resulting in the increased secretion of pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ). Meanwhile, several lines of evidence also indicated that bioengineered OMVs had satisfactory biosafety. CONCLUSION: Bioengineered OMVs fabricated in the present study were characterized by strong bladder cancer suppression and great biocompatibility, providing a new avenue for clinical bladder cancer therapy.	bladder
"Urothelial carcinoma in situ with ""overriding"" features can evade detection by mimicking umbrella cells."	"Urothelial carcinoma in situ (uCIS) is typically recognized by overtly malignant cells with characteristic nuclear features; multiple histologic patterns have been described. A rare ""overriding"" pattern, in which uCIS tumor cells extend on top of normal urothelium, has previously been mentioned in the literature, but not well described. Herein, we report 3 cases of uCIS with ""overriding"" features. Detailed morphologic evaluation revealed somewhat subtle cytologic atypia: variably enlarged hyperchromatic nuclei and scattered mitotic figures but with abundant cytoplasm and limited to superficial urothelium. Immunohistochemical (IHC) analysis showed a distinctive diffuse positive aberrant p53 pattern, limited to the atypical surface urothelial cells; these cells also showed CK20+, CD44-, and increased Ki-67. In 2 cases, there was a history of urothelial carcinoma and adjacent conventional uCIS. In the third case, the ""overriding"" pattern was the first presentation of urothelial carcinoma; therefore, next-generation sequencing molecular testing was also performed, revealing pathogenic mutations in TERTp, TP53, and CDKN1a to further support neoplasia. Notably, the ""overriding"" pattern mimicked umbrella cells, which normally line surface urothelium, can have abundant cytoplasm and more variation in nuclear and cell size and shape, and show CK20+ IHC. We therefore also evaluated umbrella cell IHC patterns in adjacent benign/reactive urothelium, which showed CK20+, CD44-, p53 wild-type, and very low Ki-67 (3/3). We also reviewed 32 cases of normal/reactive urothelium: all showed p53 wild-type IHC in the umbrella cell layer (32/32). In conclusion, caution is warranted to avoid overdiagnosis of usual umbrella cells as CIS; however, ""overriding"" uCIS should be recognized, may have morphologic features that fall short of the diagnostic threshold of conventional CIS, and requires further study."	bladder
KRT13-expressing epithelial cell population predicts better response to chemotherapy and immunotherapy in bladder cancer: Comprehensive evidences based on BCa database.	Neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) has revolutionized bladder cancer (BCa) treatment. Patients likely to benefit from these therapies need to be accurately stratified; however, this remains a major clinical challenge. In the present study, single-cell RNA sequencing was used to evaluate the predictive ability of an epithelial cell population highly expressing keratin 13 (KRT13) to assess therapeutic response in BCa. The presence of KRT13-enriched tumors indicated favorable outcomes after NAC and superior response to ICT in patients with BCa. Furthermore, KRT13 population characteristics appeared to be closely related to changes in the immune microenvironment in the vicinity of this cell population. We constructed a prognostic model using an artificial neural network based on the gene signatures in the KRT13 population; the model demonstrated strong robustness and superiority. Additionally, a user-friendly and open-access web application named BCa database was developed for researchers to study BCa by mining the connective map database.	bladder
Blood-Based Biomarkers as Prognostic Factors of Recurrent Disease after Radical Cystectomy: A Systematic Review and Meta-Analysis.	Survival outcomes after radical cystectomy (RC) for bladder cancer (BCa) have not improved in recent decades; nevertheless, RC remains the standard treatment for patients with localized muscle-invasive BCa. Identification of the patients most likely to benefit from RC only versus a combination with systemic therapy versus systemic therapy first/only and bladder-sparing is needed. This systematic review and meta-analysis pools the data from published studies on blood-based biomarkers to help prognosticate disease recurrence after RC. A literature search on PubMed and Scopus was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Articles published before November 2022 were screened for eligibility. A meta-analysis was performed on studies investigating the association of the neutrophil-to-lymphocyte ratio (NLR), the only biomarker with sufficient data, with recurrence-free survival. The systematic review identified 33 studies, and 7 articles were included in the meta-analysis. Our results demonstrated a statistically significant correlation between elevated NLR and an increased risk of disease recurrence (HR 1.26; 95% CI 1.09, 1.45; p = 0.002) after RC. The systematic review identified various other inflammatory biomarkers, such as interleukin-6 or the albumin-to-globulin ratio, which have been reported to have a prognostic impact on recurrence after RC. Besides that, the nutritional status, factors of angiogenesis and circulating tumor cells, and DNA seem to be promising tools for the prognostication of recurrence after RC. Due to the high heterogeneity between the studies and the different cut-off values of biomarkers, prospective and validation trials with larger sample sizes and standardized cut-off values should be conducted to strengthen the approach in using biomarkers as a tool for risk stratification in clinical decision-making for patients with localized muscle-invasive BCa.	bladder
Circulating and urinary tumour DNA in urothelial carcinoma - upper tract, lower tract and metastatic disease.	Precision medicine has transformed the way urothelial carcinoma is managed. However, current practices are limited by the availability of tissue samples for genomic profiling and the spatial and temporal molecular heterogeneity observed in many studies. Among rapidly advancing genomic sequencing technologies, non-invasive liquid biopsy has emerged as a promising diagnostic tool to reproduce tumour genomics, and has shown potential to be integrated in several aspects of clinical care. In urothelial carcinoma, liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) have been investigated as a surrogates for tumour biopsies and might bridge many shortfalls currently faced by clinicians. Both ctDNA and utDNA seem really promising in urothelial carcinoma diagnosis, staging and prognosis, response to therapy monitoring, detection of minimal residual disease and surveillance. The use of liquid biopsies in patients with urothelial carcinoma could further advance precision medicine in this population, facilitating personalized patient monitoring through non-invasive assays.	bladder
Real-Time Urethral and Ureteral Assessment during Radical Cystectomy Using Ex-Vivo Optical Imaging: A Novel Technique for the Evaluation of Fresh Unfixed Surgical Margins.	BACKGROUND: Our study aims to assess the feasibility and the reproducibility of fluorescent confocal microscopy (FCM) real-time assessment of urethral and ureteral margins during open radical cystectomy (ORC) for bladder cancer (BCa). METHODS: From May 2020 to January 2022, 46 patients underwent ORC with intraoperative FCM evaluation. Each specimen was intraoperatively stained for histopathological analysis using FCM, analyzed as a frozen section (FSA), and sent for traditional H&E examination. Sensitivity, specificity, positive predictive value (PPV), and the negative predictive value (NPV) of FCM and FSA were assessed and compared with H&E for urethral and ureteral margins separately. RESULTS: The agreement was evaluated through Cohen's κ statistic. Urethral diagnostic agreement between FCM and FSA showed a κ = 0.776 (p < 0.001), while between FCM and H&E, the agreement was κ = 0.691 (p < 0.001). With regard to ureteral margins, an overall agreement of κ = 0.712 (p < 0.001) between FCM and FSA and of κ = 0.481 (p < 0.001) between FCM and H&E was found. CONCLUSIONS: FCM proved to be a safe, feasible, and reproducible method for the intraoperative assessment of urethral and ureteral margins during ORC. Compared to standard FSA, FCM showed adequate diagnostic performance in detecting urethral and ureteral malignant involvement.	bladder
Identification and validation of tumor-infiltrating lymphocyte-related prognosis signature for predicting prognosis and immunotherapeutic response in bladder cancer.	BACKGROUND: It has been discovered that tumor-infiltrating lymphocytes (TILs) are essential for the emergence of bladder cancer (BCa). This study aimed to research TIL-related genes (TILRGs) and create a gene model to predict BCa patients' overall survival. METHODS: The RNA sequencing and clinical data were downloaded from the TGCA and GEO databases. Using Pearson correlation analysis, TILRGs were evaluated. Moreover, hub TILRGs were chosen using a comprehensive analysis. By dividing the TCGA-BCa patients into different clusters based on hub TILRGs, we were able to explore the immune landscape between different clusters. RESULTS: Here, we constructed a model with five hub TILRGs and split all of the patients into two groups, each of which had a different prognosis and clinical characteristics, TME, immune cell infiltration, drug sensitivity, and immunotherapy responses. Better clinical results and greater immunotherapy sensitivity were seen in the low-risk group. Based on five hub TILRGs, unsupervised clustering analysis identify two molecular subtypes in BCa. The prognosis, clinical outcomes, and immune landscape differed in different subtypes. CONCLUSIONS: The study identifies a new prediction signature based on genes connected to tumor-infiltrating lymphocytes, providing BCa patients with a new theoretical target.	bladder